This application is being completed to provide research support for a funded F31. Basic and clinical research suggests loss of estradiol following menopause may contribute to brain aging and increased risk of age-related cognitive decline and dementia. There is a great need for novel estrogenic compounds that confer positive cognitive effects without the risk of side effects. G-1 is a recently developed agonist for the novel transmembrane estrogen receptor (ER) GPR30 (Bologa et al., 2006). Activation of the GPR30 pathway is independent of either of the ER 1 or 2 pathways, raising the possibility of using G-1 as a novel estrogenic agent that lacks the risks associated with other estrogenic compounds. Previous work in our lab has shown that estradiol enhances cognitive performance in rats via effects on basal forebrain cholinergic neurons (Gibbs, 2002;Gibbs, 2007). We hypothesize that the effects of estradiol on cholinergic function and cognitive performance are mediated, in part, via effects on GPR30. The first goal of this proposal is to characterize GPR30 expression in the rat forebrain, focusing on co-expression by cholinergic neurons. Current experiments show extensive co-localization of GPR30 within cholinergic neurons in the septum, diagonal band of Broca, and nucleus basalis. GPR30 mRNA will be evaluated in these neurons using laser capture microscopy and RT-PCR. The second goal is to examine the functional effects of GPR30 activation on cholinergic neurons. Estradiol has been shown to induce activation of ERK and CREB in brain neurons and increase potassium-stimulated acetylcholine release in the hippocampus, consistent with an effect on basal forebrain cholinergic function (Gibbs et al., 1997;Levin, 2005). Our studies will evaluate rapid induction of pCREB and pERK within cholinergic neurons in response to systemic and intracerebroventricular infusions of G-1and other ER agonists. In vivo microdialysis is being used currently to evaluate the effects of G-1 and ER agonists on acetylcholine release in the hippocampus. The third goal is to test the ability of G-1 to enhance cognitive performance in ovariectomized rats comparable to the effects of estradiol. Effects of G-1 and estradiol will be compared with selective ER 1 and 2 agonists. This aim was recently completed, and G-1 was found to reverse the effects of ovariectomy on acquisition of a delayed matching to position T- maze task, similar to the effects of estradiol (Hammond et al., 2009). Current work is investigating the effects of GPR30 antagonism on this task. PUBLIC HEALTH RELEVANCE: Following menopause, women lose the neuroprotective effects of estrogen, placing them at an increased risk of developing age related cognitive decline and Alzheimer's disease, destructive neurological conditions for which no cure currently exists. Our analyses may broaden the understanding of a new pathway of estrogen signaling, laying the groundwork for the development of a new form of therapy for these diseases.